For patients age 75 and older with nonsquamous non–small cell lung cancer (NSCLC) not previously treated with chemotherapy, combination carboplatin and pemetrexed followed by pemetrexed maintenance is both effective and tolerable, suggest the results of a phase 3 trial.
The median overall survival was 18.7 months for patients randomized to carboplatin/pemetrexed and 15.5 months for patients randomized to docetaxel monotherapy.
The combination met the prespecified endpoint for noninferiority to docetaxel but was not shown to be superior in terms of overall survival, investigator, of Kyushu University in Fukuoka, Japan, and colleagues reported in .
Still, progression-free survival was significantly longer in the carboplatin/pemetrexed arm, and dose reductions were less frequent with the combination than with docetaxel.
“The combination of carboplatin and pemetrexed followed by pemetrexed maintenance ... provides a clinically significant benefit with regard to its effectiveness and tolerability,” the investigators wrote. “This combination should therefore be considered as a standard option for treatment in this setting.”
Dr. Okamoto and colleagues noted that the lung cancer incidence in elderly patients – 75 years and older – is increasing, and cytotoxic chemotherapy remains the standard treatment for patients whose tumors do not carry targetable mutations or are resistant to immunotherapy.
“In anticipation of a further increase in the number of elderly individuals with advanced NSCLC, it will be important to develop more optimal chemotherapeutic regimens for this patient group,” the investigators wrote.
To that end, they conducted a phase 3 trial of carboplatin/pemetrexed in patients aged 75 and older with NSCLC who had not been exposed to cytotoxic chemotherapy.
Patients and treatment
There were 433 patients enrolled in the trial. Their median age was 78 years (range, 75-88 years), and 57.7% were men. All patients had Eastern Cooperative Oncology Group performance status of 0 or 1.
Patients were stratified by clinical stage (III, IV, or recurrence), sex, epidermal growth factor receptor variant status (wild-type, exon 19 deletion, L858R variant of exon 21, or unknown), and treatment center.
The patients were then randomly assigned on a 1:1 basis to receive either intravenous docetaxel at 60 mg/m2 for 60 minutes on day 1 every 3 weeks or pemetrexed at 500 mg/m2 for 10 minutes followed by an infusion of carboplatin at an area under the curve of 5 for 30 minutes on day 1 every 3 weeks. The combination therapy was repeated for up to four courses and followed by 3-week courses of maintenance therapy with the same dose of pemetrexed.
Both regimens were continued until disease progression or the development of unacceptable toxicities.
Efficacy and safety
All 433 randomized patients were included in the efficacy analysis, but the safety analysis included 428 patients. Three patients assigned to docetaxel and two assigned to carboplatin/pemetrexed did not receive protocol treatment.
The respective median overall survival for the docetaxel and carboplatin/pemetrexed arms was 15.5 months and 18.7 months, which translated to a stratified hazard ratio for death of 0.85, meeting the prespecified noninferiority endpoint (P = .003).
However, the upper limit of the 95% confidence interval was 1.056, exceeding the prespecified superiority margin of 1.000. Therefore, the combination could not be proven superior to docetaxel with regard to overall survival.
On the other hand, progression-free survival was significantly longer with carboplatin/pemetrexed. The median progression-free survival was 6.4 months in the combination arm and 4.3 months in the docetaxel arm (unstratified HR, 0.739; P < .001).
The overall response rate with carboplatin/pemetrexed was 36.8%, compared with 28.2% for docetaxel, but this difference was not statistically significant.
Adverse events that were more common in the docetaxel arm than in the combination arm included grade 3/4 decreases in white blood cell count (68.7% and 28%, respectively), grade 3/4 decreases in neutrophil count (86% and 46.3%, respectively), and febrile neutropenia (17.8% and 4.2%, respectively).
Adverse events more frequently seen with the combination than with docetaxel included anemia (29.4% and 1.9%, respectively) and decreased platelet counts (25.7% and 1.4%, respectively).
Two patients in each arm died from treatment-related causes. In the docetaxel arm, the deaths were caused by acute respiratory distress syndrome and pneumonitis. In the combination arm, the deaths were caused by dyspnea and pneumonitis.
Approximately 29% of patients in each arm reported improvement in quality of life at 18 weeks, compared with baseline.